tbuckley/cabot-search huggingface dataset:
Abstract 10845: Akt-Dependent Vacuolar Protein Sorting 34 Activation Promotes Pulmonary Vascular Smooth Muscle Cell Proliferation and Survival in Pulmonary Hypertension
Authors: Yuanjun Shen, Dmitry Goncharov, Lifeng Jiang, Derek Lin, Theodore Avolio, Evelyn Okorie, Ana L Mora, Aisha Saiyed
Journal: Circulation (2022)

Introduction: Pulmonary arterial hypertension (PAH), a deadly disease with no cure, manifests by small PA remodeling, leading to increased PA pressure and right ventricular (RV) afterload, heart failure, and death. Pulmonary vascular remodeling is characterized by increased proliferation and survival of resident PA vascular cells, the mechanisms of which are not fully understood. Class III phosphatidylinositol 3-kinase vacuolar protein sorting 34 (Vps34) promotes cell hyper-proliferation in cancer. The status and mechanisms of regulation and function of Vps34 in PA vascular cells in PAH are not clear. Methods/Results: Immunohistochemical analysis showed that inhibitory Ser164 phosphorylation of Vps34 (P-Ser164-Vps34) was significantly decreased in smooth muscle alpha-actin (SMA)-positive areas of small remodeled PAs from PAH patients compared to PAs from non-diseased donors. Immunoblot (IB) analysis of human PA vascular smooth muscle cells (PAVSMC) from small PAs further demonstrated that P-Ser164-Vps34 is significantly decreased in human PAH PAVSMC. Similar to human PAH, we detected a significant decrease of P-Ser164-Vps34 in SMA-positive areas of small remodeled PAs from mice and rats with SU5416/hypoxia-induced PH, which was associated with increased PA medial thickness, RV pressure, and RV hypertrophy. IB analysis of PAH PAVSMC with Akt inhibitor VIII treatment or Akt-knockdown by specific siRNA demonstrated that Vps34 activation is Akt-dependent, which is associated with TSC2 deficiency, Vps15 over-accumulation, and increased proliferation and survival. Pharmacological inhibition of Vps34 in PAH PAVSMC by selective inhibitors SAR405 and VPS34-IN1 significantly decreased proliferation (Ki67) and induced apoptosis (TUNEL). Two-week treatment of SAR405 in mice with SU5416/hypoxia-induced PH attenuated pulmonary vascular remodeling. The above results suggest a therapeutic potential of Vps34 inhibition to reduce PAH PAVSMC hyper-proliferation and attenuate pulmonary vascular remodeling in PAH. Conclusions: Akt-dependent Vps34 activation supports proliferation and survival of PAH PAVSMC. Further studies are needed to evaluate the therapeutic potential of Vps34 inhibition against PAH.
Abstract 10757: Machine-Learning Models Based on Real-World Data to Predict Rehospitalization or Death After Acute Myocardial Infarction
Authors: George Seegan, James O’Kelly, Bethany Kalich, Ahva Shahabi
Journal: Circulation (2022)

Introduction: Prospectively identifying patient characteristics associated with myocardial infarction (MI) readmission would help target patients at high risk of recurrent events for improved clinical management. This study aimed to build and evaluate machine learning models based solely on real world data to identify predictors of rehospitalization or death within one year following acute MI. Methods: The study population consisted of adult patients who experienced a first hospitalization for MI between January 1, 2013 and December 31, 2017 in the Optum® Clinformatics® Data Mart, an administrative health claims database from a large US national managed care company. Logistic Regression (LR), Extreme Gradient Boosting (XGBoost), and Deep Neural Network (DNN) models were developed and tested. Model variables included patient demographics, clinical characteristics, and specific treatments. Variable importance for model prediction was ranked. Results: Among 96,244 patients who had an initial MI, 15,925 (16.5%) had rehospitalization/death within a year. The LR, XGBoost, and DNN models performed similarly (area under the curve 0.762, 0.774, and 0.785 respectively). The XGBoost was selected as the primary model to assess the relative importance of the variables in predicting MI rehospitalization/death. Of the most impactful variables, older age, higher Charlson Comorbidity Index, presence of chronic kidney disease (all stages), previous heart failure, and no previous coronary arterial bypass graft were highly predictive of MI rehospitalization/death (Figure). Conclusions: The machine learning models developed in this study can be implemented within clinical systems to identify patients at high risk for MI readmission to improve care and decision-making. However, these models require external validation in other datasets. Furthermore, performance of the models might be improved by including information such as LDL-C levels and PCSK9 inhibitor use.
Abstract 10477: Newer Guideline-Directed Medical Therapies Are Underutilized in 2021-22 in Patients With Heart Failure Without Diabetes
Authors: Mario Enrico Canonico, Judith A Hsia, Christopher P Cannon, Marc P Bonaca
Journal: Circulation (2022)

Introduction: In 2021-22, Heart Failure (HF) guidelines endorsed quadruple therapy with beta blockers (BB),angiotensin-converting inhibitors/angiotensin receptor blockers (ACEi/ARB) or angiotensin receptor-neprilysin inhibitors (ARNI), mineral receptor antagonists (MRA) and sodium-glucose cotransporter-2 inhibitors (SGLT2i) as first-line medications to improve clinical outcomes. AHA 2022 HF guidelines specifically recommended SGLT2i even in patients without diabetes mellitus (DM) irrespective of left ventricular ejection fraction (HF). Hypothesis and Methods: Our analysis evaluated the hypothesis that prescription of guideline directed medical therapy (GDMT) is similar in patients with or without DM. We extracted TriNetX data for patients with HF encounters from May 2021-April 2022 in the University of Colorado health system which includes an ethnically diverse population of rural and urban residents. Patient on dialysis were excluded. GDMT use was compared by chi square. Results: Among 24890 patients with HF encounters, 9240 (37%) had reduced (HFrEF) and 8680 (35%) preserved ejection fraction (HFpEF) and 6970 (28%) unspecified HF. Mean age was 70 + 14y, 46% were female, 10% Latino in the whole cohort. Diagnosed DM was reported among 3260 (35%) with HFrEF and 3410 (39%) with HFpEF. Older drugs such as BB and ACEi/ARB were widely prescribed in both groups, particularly among patients with DM (Figure, p&lt;0.0001 for both drug classes). MRA were less often prescribed, particularly among patients without DM (Figure, p=0.0089 in HFrEF and p&lt;0.0001 in HFpEF). No difference in ARNI use was detected in patients with vs without DM. SGLT2i prescription was particularly low in patients without DM regardless of HF phenotype (Figure, both p&lt;0.0001). Conclusion: Even in 2022, patients without DM were less likely than those with DM to receive BB, ACEi/ARB, MRA and SGLT2i. Efforts to improve use of GMDT for HF could target patients without DM.
Abstract 10824: Pulsatile Ventricular Assist Device Prior to Pediatric Heart Transplantation is Associated With Favorable Post-Transplant Hemodynamics
Authors: Hanna John J Tadros, Susan W Denfield, Athar Qureshi, Kyle Hope, Kriti Puri, Jack Price, Hari P Tunuguntla, Swati Choudhry, Iki Adachi, William Dreyer, Joseph Spinner
Journal: Circulation (2022)

Background: Ventricular assist device (VAD) support is increasingly used in end-stage pediatric heart failure management. The effects of pulsatile VAD (PVAD) and continuous-flow VAD (CVAD) support on hemodynamics (HDS) after pediatric heart transplant (HT) are unknown. We compared the difference in post-HT HDS between patients supported with PVAD vs CVAD. Methods: We collected measures of pulmonary vascular resistance index (PVRi), cardiac index (CI), and pulmonary wedge pressure (PCWP) in the 1 st year post-HT among patients that underwent HT at our institution between 2013-2020. We defined normal HDS as a PVRi &lt; 3Wu/m 2 , CI &gt; 2.5L/min/m 2 , and PCWP &lt; 12mmHg. Linear regression analysis and Cox regression were performed to compare differences in HDS post-HT. Results: Demographics/clinical features of the patients supported with PVAD (n=18) and CVAD (n=41)are described in Table 1. PVR, CI, and PCWP are plotted in Figure 1. Accounting for confounders, the mean PCWP over the 1 st year is lower in the PVAD group (-0.83 [-1.72-0.07], p=0.07) while the mean CI and mean PVR are similar. In the PVAD cohort, 16 (89%) had normalized HDS in the 1st year vs 17 (42%) in the CVAD group (Log Rank: p&lt;0.001). In multivariate analysis, PVAD was the only variable associated with normalization of HDS (HR 3.87 [1.03-14.52], p=0.045). Compared to our non-VAD cohort (n=97), patients with PVAD were as likely to have HDS normalization by 1 year, but CVAD patients trended towards being less likely to normalize (HR 0.58, p=0.08). Conclusion: Patients supported with PVAD pre-HT have lower PCWP and were more likely to achieve normalization of HDS post-HT compared to patients supported with CVAD.
Abstract 11037: Inappropriate Sinus Tachycardia and <sup>18</sup> FDG PET Scan
Authors: Nourhan Chaaban, Said Chaaban, Shilpa Kshatriya
Journal: Circulation (2022)

Introduction: Inappropriate sinus tachycardia is a clinical syndrome characterized by an elevated heart rate at baseline with associated symptoms including palpitations. This entity can be quite disabling with no identifiable etiology in most cases. However, secondary causes need to be evaluated. This case highlights the utility of 18 F-Fluorodeoxyglucose PET in identifying myocarditis in a patient with systemic lupus erythematosus and in therapy changing management. Case: A 30-year-old female presented to the cardiology clinic with symptoms of palpitations for the past year with associated dizziness and fatigue, impairing her quality of life. Past medical history includes SLE, maintained on Hydroxychloroquine, and antiphospholipid antibody syndrome on warfarin. A resting EKG showed sinus tachycardia. Medical workup for sinus tachycardia was unremarkable. The patient had a normal echocardiogram. A 24-hour Holter monitor showed occasional PACs, a maximum HR of 167 with an average HR of 102 bpm, with symptoms of lightheadedness and palpitations correlating with sinus tachycardia (rates of 106 to 134 bpm). A treadmill exercise test was negative for ischemia with a peak HR of 196 bpm. Given suspicion for autoimmune myocarditis, an FDG PET using F18 was ordered showing abnormal di!use FDG myocardial uptake consistent with inflammation. The patient was started initially on metoprolol tartrate. She developed side e!ects, so she was switched to ivabradine and diltiazem. These findings were also communicated to her rheumatologist with a decision to aggressively treat her lupus disease. Methotrexate and a prednisone course were added. After 2 months, the patient reported improvement to near resolution of her symptoms. Conclusion: In this case, we aim to introduce the importance of cardiac PET nuclear imaging in addressing the relationship between inappropriate sinus tachycardia and autoimmune disease.
Abstract 10825: Tumor-Bearing Induces Cardiomyopathy by Disrupting Cardiometabolic Reprogramming
Authors: Ming Yang, shijie xiong, Jing Tan, yuanlong li, Conghui Shen, Teng Wu, xinlu fu, ziqi feng, yuanjun ji, huiting zheng, weibin cai
Journal: Circulation (2022)

Introduction: Advances in cancer therapies have significantly improved patient survival. However, prolonged tumor-bearing (TB) survival makes the originally hidden cardiovascular disease become an increasingly important cause of death in tumor patients. In addition, some commonly used chemotherapeutic agents, such as the doxorubicin (DOX), have definite cardiotoxicity. Moreover, epidemiological studies found higher risks of cardiovascular disease in cancer patients than in the general population. This study aimed to investigate the if the TB state leads to cardio-fragility and myocardial sensitivity which further causes excessive cardiotoxicity of DOX in tumor patients. Methods and Results: We established mouse TB models with six types of transplantation tumors. We administrated them and littermate controls with DOX intraperitoneal injections of 10mg/kg weekly for four weeks. The results showed more severer myocardial injury in TB mice than control group based on the echocardiography, cardiac fibrosis, and etc. The RNA-seq, extracellular flux analysis, and PET-CT indicated an increased proportion of myocardial glycolytic metabolism in the TB state. Furthermore, the Secretomic results of clinical cancer patients and control group, along with the Co-IP of TB mice, showed that the TB state induced hyper-phosphorylation of protein tyrosine residues in cardiomyocytes (CMs) via the increase of secreted growth factors, which introduced an elevated expression of pyruvate kinase muscle 2 (PKM2) and increased the proportion of dimer conformation. Meanwhile, those changes allowing re-entry of CMs into the cell cycle and further increased DNA damage co-localization with EdU, eventually led to excessive cardiotoxicity in the TB state by DOX. Finally, treatment with AG-1478 or TEPP-46 with DOX restricted the cardiotoxicity in the TB state, which meanwhile enhanced the tumor-suppressive effect in lung cancer and melanoma models. Conclusion: Our study reveals that differences in tyrosine phosphorylation of CMs between TB and normal states could cause metabolic pattern shift and cell cycle re-entry in CMs. The increased cardio-fragility induced by TB state may be involved in the enhanced cardiotoxic side effects of chemotherapeutics.
Abstract 11843: Association of Individual- And Neighborhood-Level Factors With Racial and Ethnic Differences in Cardiovascular Health During Early Pregnancy
Authors: Natalie A Cameron, Xiaoning Huang, Lucia C Petito, Hongyan Ning, Nilay S Shah, Lynn M Yee, Amanda M Perak, Jin K Kim, David Haas, Brian M Mercer, Samuel Parry, George R Saade, Robert M Silver, Hyagriv N Simhan, Ronald J Wapner, Philip Greenland, Donald M Lloyd-Jones, Kiarri N Kershaw, William A Grobman, Sadiya S Khan
Journal: Circulation (2022)

Introduction: Individual and neighborhood-level factors are associated with racial and ethnic differences in cardiovascular health (CVH). To identify strategies to improve maternal health, we determined the relative contributions of these factors to racial and ethnic differences in early pregnancy CVH. Methods: We included pregnant individuals from nuMoM2b, a multicenter cohort who self-identified as Hispanic, non-Hispanic Black (NHB), or non-Hispanic White (NHW). We applied a Blinder-Oaxaca decomposition to evaluate the extent to which socioeconomic and psychosocial factors, discrimination experiences, and area deprivation index statistically explain racial and ethnic differences in CVH (0-8 points, based on body mass index, blood pressure, diabetes, and smoking status) in the first trimester. This method utilizes a counterfactual approach to estimate the mean change in CVH in the Hispanic and NHB groups if covariates were set to the mean in the referent group (NHW). We calculated the percent explained by each factor by dividing the predicted mean change by the total CVH difference between groups*100. Results: Of 5,695 pregnant individuals, 12.3% were Hispanic, 8.9% NHB and 78.8% NHW. Mean CVH scores were 6.4 for Hispanic, 6.0 for NHB and 6.6 for NHB individuals. After adjusting for age and immigrant status, mean CVH scores were lower (worse) by 0.83 (95% CI 0.51-1.04) points in NHB individuals and 0.49 (95% CI 0.28-0.60) points in Hispanic individuals compared with NHW individuals. Differences in social and psychologic factors explained 87% of NHB-NHW differences and 71% of Hispanic-NHW differences in CVH scores (FIGURE) ; socioeconomic factors explained the greatest difference in CVH between groups. Conclusions: Individual- and neighborhood-level social and psychologic factors statistically explained a clinically meaningful difference in CVH among racial and ethnic groups, which may inform strategies to optimize health in pregnant individuals.
Abstract 10490: Sex Disparities in Cardiovascular Research Are Influenced by Senior Investigator Gender
Authors: Stefan Veizades, Natasha Auer, Jaylen Sandifer, Adrienne Mueller, Carlos D Vera, Patricia K Nguyen
Journal: Circulation (2022)

Introduction: The clinical presentation and management of cardiovascular diseases has been shown to be sex-specific, yet, historically, cardiovascular research participants have been predominantly male. One cause for this discrepancy could be gender-based bias on the part of studies' senior investigators. Methods: We screened 749 randomly selected clinical research articles from 8 top cardiovascular research journals, published between 2015 and 2020. We predicted the gender of senior investigators by using the genderize.io gender-coding algorithm. We then used t-tests to determine the relationship between putative senior author gender and number of study participants of each sex. Results: Cardiovascular research cohorts were 39.74% female. Compared to studies senior-authored by men, cohorts of female senior-authored studies included 11.36% more female participants (p&lt;0.0001, 37.84% vs 49.44%). This difference was preserved across several study types ( Fig. 1A ). Only 15.49% of articles were written by female senior authors and the proportion of female to male senior authors did not change over time (p=0.93; Fig. 1B ). The proportion of female participants in a study did however significantly increase between 2015 and 2020 (p=0.011, Fig. 1B ). Conclusions: In cardiovascular research, the gender of the senior author of a study is predictive of the study’s sex composition: female senior authors are more likely to author studies that include higher proportions of female participants. Over time, the proportion of female to male participants in cardiovascular research studies is increasing. Figure 1. Percentage of women in study cohorts, ( A ) segregated by study type and gender of senior author and ( B, right ) segregated by senior author gender and year. ( B, left ) Percent of female seniors by year. Bars represent mean and standard error. p&gt;0.05=ns, p≤0.05=*, p≤0.01=**, p≤0.001=***, p≤0.0001=****.
Abstract 106: Neurological Effects Of Methylene Blue In A Porcine Model Of Cardiac Arrest
Authors: Cecilie M Johannsen, Casper Nørholt, Cecilie Baltsen, Mark Andreas A Eggertsen, Andreas Magnussen, Lasse Vormfenne, Signe Ø Mortensen, Lauge Vammen, Lars W Andersen, Asger Granfeldt
Journal: Circulation (2022)

Purpose To investigate the neuroprotective effects of methylene blue (MB) in a clinically relevant porcine model of cardiac arrest. Method: 40 anaesthetized pigs were subjected to myocardial infarction and seven minutes of untreated cardiac arrest. Animals were randomized into three groups: one group received saline only (control), one group received 2 mg/kg MB and saline (MB+saline), and one group received two doses of 2 mg/kg MB (MB+MB). The first intervention was given after the 3rd rhythm analysis, while the second dose was administered one hour after achieving return of spontaneous circulation (ROSC). The main investigator was blinded during resuscitation and the first hour after ROSC. Animals underwent intensive care and observation for 6 hours. Neurological outcomes were evaluated by cerebral microdialysis and serum-neuron specific enolase (NSE). Normality was assessed by qq-plot and histograms. Pointwise data were analyzed using Kruskal-Wallis test as data did not assume normal distribution. Data are presented as medians and 25 th and 75 th percentiles. A value of p&lt;0.05 was considered statistically significant. Results: The proportion of animals achieving ROSC was similar across groups: 11/13 (85%) in the control group, 10/13 (77%) in the MB+saline group, and 12/14 (86%) in the MB+MB group (p=0.81). Cerebral lactate and pyruvate levels increased after ROSC in all groups. Lactate/pyruvate ratios were comparable between groups two hours after ROSC (control: 25 (22;31); MB+saline: 24 (22;36); MB+MB: 23 (20;28); p=0.43). Cerebral glycerol levels initially increased in all groups with the highest levels at two hours after ROSC (control: 454 μmol/L (319;507); MB+saline 351 μmol/L (241;420); MB+MB 347 μmol/L (256;478); p=0.35). Glycerol levels decreased over time with no difference 6 hours after ROSC (control: 210 μmol/L (138;293); MB+saline (146 μmol/L (61;156); MB+MB: 105 μmol/L (63;159); p=0.07). Serum-NSE levels 6 hours after ROSC were not different between groups (control: 0.9 μg/L (0.7;1.5); MB+saline 1.5 μg/L (1.0;2.0); MB+MB: 1.0 μg/L (0.7;1.2); p=0.13). Conclusion Contrary to previous publications the current porcine trial did not observe any neuroprotective effects of MB when evaluated by cerebral microdialysis and NSE levels.
Abstract 11030: Decreased CD34 <sup>+</sup> Cell Count is Associated With Coronary Allograft Vasculopathy in Heart Transplant Recipients
Authors: Gregor Poglajen, Laura Poljancic, Rok Zbacnik, Sabina Frljak, Gregor Zemljic, Andraz Cerar, Nea or, Renata Okrajek, Miran Šebetjen, Bojan Vrtovec
Journal: Circulation (2022)

Introduction: The underlying mechanisms of coronary allograft vasculopathy (CAV) after heart transplantation remain incompletely understood. Hypothesis: As CD34 + cells represent one of the key determinants of coronary vascular homeostasis we investigated the potential association between CAV and CD34 + cell count in heart transplant recipients. Methods: In a single-center prospective pilot cohort study we included 59 adult heart transplant recipients without history of congenital heart disease, multi-organ transplantation or oncologic therapy. All patients underwent coronary CT angiography and the presence of CAV was defined in accordance with the ISHT criteria. At the time of CT angiography, we collected blood samples and measured CD34 + cell count using Beckman-Coulter Navios EX flow cytometry with standard antibodies according to ISAGE protocol as well as biomarkers of angiogenesis using Luminex assay kit. Results: CAV was present in 15 patients (25%; Group A) and absent in 42 patients (75%; Group B). The two groups did not differ in age (62±11 years in Group A vs. 60±11 years in Group B, P=0.56), gender (male: 100% vs. 80% in Group B, P=0.07), heart failure etiology (ischemic: 53% vs. 43%, P=0.50), presence of hypertension (60% vs. 63%, P=0.80), diabetes (33% vs. 25%, P=0.54) or renal insufficiency (53% vs. 43%, P=0.50). Also, donor age (44±14 years in Group A vs. 43±12 years in Group B, P=0.66), allograft ischemic time (202±72 min vs. 190±68 min, P=0.57), tacrolimus trough levels (8.8±3.8 μg/L vs. 7.4±1.9 μg/L, P=0.14), MMF dose (2067±442 mg vs. 2178±606 mg; P=0.52) and statin therapy (86% vs. 75%; P=0.36) were comparable. While total leukocyte count was similar in both groups (7.7±2.1x10 9 /L in Group A vs. 6.8±2.2x10 9 /L in Group B, P=0.60), we found significantly lower CD34 + cell count in Group A compared to Group B (1.33±0.45x10 6 /L vs. 2.23±1.45x10 6 /L, P=0.02). Conversely, VEGF serum levels were significantly lower in Group A than in Group B (0.09±0.06 ng/L vs. 0.14±0.09 ng/L; P=0.03). Conclusions: Decreased CD34 + cell count and increased VEGF serum levels appear to be associated with CAV in heart transplant recipients. Further studies are warranted to investigate the potential of CD34 + cells in prevention and treatment of CAV in this patient cohort.